The HIV/AIDS pandemic has led to illness and early death for millions of adults, and this, in turn, has left many millions of orphans in sub-Saharan Africa. In Kenya, alone, there are more than 2.4 million orphans who are at great risk for school dropout, early sexual debut, and HIV infection. Approaching the fourth decade of the AIDS epidemic, many in the field have called for a paradigm shift in HIV prevention, to address structural, as well as individual-level, factors. This study examines the impact of school support as a structural intervention, tested among adolescent Luo orphans in Nyanza Province, Kenya. The Luos have the highest HIV prevalence and largest orphan prevalence of all ethnic groups in the country. The study uses a rigorous randomized controlled trial design to test whether school support can retain adolescent orphans in school through the transition to high school, delay sexual debut, and reduce the likelihood of HIV and herpes simplex virus type 2 (HSV-2) infections. Specific aims for the proposed study are: 1) To experimentally test whether providing comprehensive school support to Luo orphaned boys and girls will reduce school dropout, reduce sexual risk behaviors, and prevent HIV/HSV-2 infection;2) To conduct a process evaluation of the implementation of the program;and 3) To conduct comparative cost effectiveness analyses, specifying the intervention's cost and return on investment as evidenced by cost per unit improvement in the primary outcomes of school enrollment, delay of sexual debut and prevention of risk behaviors and HIV/HSV-2 infection, as well as by gains in health- related quality of life. The design randomizes 24 primary schools to intervention or control condition. All youth in grades 7 and 8 who have lost one or both parents, regardless of cause of death, will be invited to participate;the total number of participants to be recruited into the study is approximately 840 students, 420 in each condition. Youth in intervention schools will receive five years of school support, including tuition, fees, uniforms, and a school-based adult "helper." Data will comprise annual ACASI surveys, school data (attendance, grades), and HIV/HSV-2 bio-specimens. Analyses will test posited mediators and gender moderation in causal pathways and program effects. Cost effectiveness analyses will add much needed policy-relevant information. PUBLIC HEALTH RELEVANCE: Although millions of children have been orphaned as a result of the AIDS pandemic, few studies have considered the particular vulnerability of young orphaned adolescents for school dropout, risky sexual behaviors, and HIV infection. The Luo people of Nyanza Province have the highest proportion of orphans, highest HIV prevalence, and earliest sexual debut among all ethnic groups in Kenya. This structural intervention trial uses a strong conceptual framework and rigorous experimental design to test whether school support can keep adolescent Luo orphans in school, reduce sexual risk behaviors, and prevent HIV /HSV-2 infection. Process evaluation and cost effectiveness analyses add further relevance for policy development.